JP2018532755A - Method for treating acne vulgaris using a topical dapsone composition - Google Patents

Abstract

The dapsone composition can be useful for treating acne. The methods and formulations disclosed herein show efficacy in the treatment of acne vulgaris and / or post-inflammatory pigmentation.
[Selection figure] None

Description

This application is related to US Provisional Application No. 62 / 250,763 filed Nov. 4, 2015 and US Provisional Application No. 62 / 299,978 filed Feb. 25, 2016. The entire contents of both applications are incorporated herein by reference.

FIELD Embodiments of the present invention generally relate to methods of treating acne vulgaris and / or post-inflammatory pigmentation with topical dapsone compositions.

  Acne is a group of common skin symptoms characterized by so-called “acne-like” or acne-like rashes, which can be contaminated by bacteria, such as Propionibacterium acnes, and are characterized by inflammation Sometimes it is. Acne tends to occur in the most active skin areas of the sebaceous glands, such as the face. Acne is associated with trauma and can result in scar formation and loss of aesthetics if left untreated.

  The classification and diagnosis of various acne symptoms can be complex and even inconsistent. Because of this complexity and unpredictability, drug therapies and other therapies are often developed on a trial and error basis to determine the most effective course of treatment for a particular patient. The results of any particular acne treatment plan will vary greatly from patient to patient and throughout the treatment of a particular patient. In addition to the complexity and variability of acne symptoms, treatment effectiveness can be greatly affected by patient adherence to treatment plans. Patient compliance during acne treatment can be affected by side effects (generally including redness, pruritus and dermabrasion in the case of topical medications). The complexity of the dosing schedule can also adversely affect patient compliance, especially when two or more different topical medications are prescribed simultaneously. Another factor that adversely affects patient compliance is the cost of the dosing plan, which can be very expensive when a large number of medications are prescribed. In some countries, acne is considered a cosmetic problem and insurance is not applied to the treatment of acne, thus further increasing the cost of treating the patient. Specific compositions for the treatment of acne are available. Many of the available compositions contain one active agent known to have anti-acne activity. The stability of a composition containing a large number of anti-acne agents can be problematic. Also, these compositions can be difficult to manufacture.

  Thus, there continues to be a need for compositions and methods used in the treatment of acne, where topical application is potentially effective. The compositions and methods provided herein address these and other needs in the art.

  Dapsone (4,4'-diaminodiphenyl sulfone) is a drug with several beneficial pharmaceutical activities. Dapsone is typically administered as one of the drugs used in the treatment of leprosy. Dapsone and its derivatives are also effective in the treatment of bacterial infections, protozoal infections such as malaria and pneumocystis carinii, and plasmonic infections such as toxoplasma infections.

  Dapsone is also useful as an anti-inflammatory agent. It is intended to treat skin diseases characterized by abnormal infiltration of neutrophils, such as herpes zoster, linear IgA dermatosis, pustular psoriasis, necrotizing pyoderma, acne vulgaris and Sweet syndrome Have been used. Examples of dapsone formulations useful in the present application are found in US Pat. No. 9,161,926, which is incorporated herein by reference in its entirety.

  The use of dapsone topical compositions can be problematic. The topical composition can act as a skin desiccant. It removes essential oils and natural emollients from the skin, thus leading to dryness, itching and cracking of the skin. However, exogenous emollients, oils, etc. cause phase separation and dapsone precipitation. The use of common emulsifiers does not resolve dapsone precipitation because of the reduced solubility of dapsone and the competing physical properties of the resulting composition phase. There is a particular need for topical compositions and methods comprising dapsone that will exhibit, for example, improved efficacy, reduced side effects, or both when used in certain patients with skin conditions. Such improved topical compositions comprising dapsone and methods of use thereof are also needed to improve the treatment of patients with acne or suspected acne. The methods of the invention using dapsone formulations can be useful for treating various dermatological conditions. Some useful compositions include dapsone in a polymeric viscosity improver. Some compositions can be adjusted to optimize dapsone skin delivery to effectively treat dermatological conditions and improve the effectiveness of pharmaceutical products applied to the skin. Diethylene glycol monoethyl ether is a solubilizing agent for dapsone, which makes it possible to prepare a composition having an improved solubility of dapsone. As a result, the compositions described herein are effective in treating dermatological symptoms in a subject in need of treatment of subcutaneous symptoms.

  In one embodiment, the composition comprises dapsone, a first solubilizer that is diethylene glycol monoethyl ether, an optional at least one second solubilizer, a polymer viscosity improver, and water. Wherein the dapsone is present at a concentration of about 5% to about 10% by weight.

  In one embodiment, the composition comprises dapsone, a first solubilizer that is diethylene glycol monoethyl ether, an optional at least one second solubilizer, a polymer viscosity improver, and water. The composition is provided wherein dapsone is present at a concentration of about 3% to 8% by weight.

  In another embodiment, a method for treating a dermatological condition is provided. Such methods can be practiced, for example, by administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition described herein.

  In some embodiments, a method of treating acne vulgaris is provided by administering a 7.5 wt% dapsone formulation once a day. In some embodiments, the method significantly reduces the number of lesions over a period ranging from 2 to 12 weeks. In some embodiments, treatment reduces the incidence of adverse events such as erythema, scaling, dryness and / or tingling / burning. In some embodiments, the method results in very few cases (eg <1%) of redness, dryness and exfoliation of the treated skin.

  In some embodiments, a method of treating acne vulgaris in a subject in need of acne vulgaris treatment comprises applying a topical pharmaceutical composition comprising about 7.5% by weight dapsone to acne vulgaris. Administration to the entire face of the subject once a day for a treatment duration effective to improve The duration of treatment can range from about 4 weeks to about 12 weeks. The method can be therapeutically effective in reducing the number of facial lesions in a subject. In some embodiments, the topical pharmaceutical composition does not include adapalene. According to one embodiment, the treatment duration is 12 weeks. In some embodiments, the lesion is an inflammatory lesion. In some embodiments, the lesion is a non-inflammatory lesion. According to some embodiments, the method is effective in reducing the amount of topical skin irritation in a subject over the duration of treatment.

  In some embodiments, the local skin irritation comprises erythema. In some embodiments, the local skin irritation includes scaling. According to some embodiments, the topical skin irritation includes dryness. In some embodiments, the local skin irritation comprises tingling / burning. In some embodiments, the topical pharmaceutical composition further comprises about 30% by weight diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition further comprises 4% by weight of a polymeric viscosity improver composed of an acrylamide / acryloyldimethyltaurine sodium copolymer. In some embodiments, the topical pharmaceutical composition further comprises methyl paraben.

FIG. 3 shows the average rate of decrease from baseline of acne vulgaris over time when the formulation of the present invention is compared to vehicle when administered once a day. The local skin irritation over time (at baseline, maximum severity and at the end of the 12 week treatment regimen) when the formulations of the present invention were administered once a day to treat acne vulgaris It is a chart shown.

DETAILED DESCRIPTION It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive of the scope of the claims. As used herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, “or” means “and / or” unless stated otherwise. Further, the term “including” and other forms, such as “includes” and “included”, are non-limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

  Some embodiments include compositions and products for treating skin conditions, and methods for treating skin conditions. As used herein, the term “skin condition” encompasses a condition, disorder or disease affecting human and animal skin. Such skin conditions include, but are not limited to, for example, symptoms associated with skin inflammation, symptoms involving sebaceous glands and hair follicles, symptoms characterized by acne-like symptoms, and skin dryness, skin thickening, skin scaling or skin Symptoms accompanied by peeling are included. Skin conditions that can be treated using some of the compositions, products and methods described herein include, but are not limited to, acne, rosacea, folliculitis, perioral dermatitis, photodamage , Skin aging, psoriasis, ichthyosis, atopic dermatitis, treatment of chronic wounds, bedsores, pore keratosis, scars (including scars due to surgery and acne), sebaceous cysts, inflammatory skin diseases, post-inflammatory pigments Deposition, eczema, dryness, pruritus, lichen planus, nodular rash, eczema and rash.

  As used herein, the term “acne” encompasses skin conditions with acne-like or acne-like symptoms. For example, skin conditions characterized by follicular rashes such as papules and pustules that resemble acne can be classified as acne. It should be understood that the term “acne” is not limited to diseases and symptoms characterized by papules and pustules, but can be characterized by various symptoms. Also, certain patients with acne can be in remission, or the patient's acne can be managed by continuing treatment, and therefore the patient has few or no symptoms It should also be understood that it is possible. Nevertheless, it may be recommended to continue acne treatment in such patients to reduce the likelihood of recurrence of acne symptoms.

  Acne symptoms or acne-like symptoms include, but are not limited to, the appearance of various skin lesions. The term “lesion” is usually used to describe an infected or diseased skin part. The lesion may be accompanied by infected sebaceous glands. Some lesions are more severe than others. Examples of skin lesions are comedones, spots, papules, pustules, nodules and cysts. The term “comedo” (plural form “comedones”) is used to describe sebaceous pores clogged with dirt, other cells, fine hair or bacteria. The comedones include so-called “black acne”, sometimes called “open comedones”, which have spots or surfaces that appear black. The comedones also include “white acne” with slightly inflamed skin-colored bumps and spots or surfaces that appear white. The term “stain” usually refers to flat spots or areas of discolored skin, such as red spots. The term “pustules” is usually used to refer to inflammatory lesions filled with pus of skin or inflammatory ridges filled with pus. The term “papules” is usually used to refer to a small, hard, mostly inflammatory, pus-free skin ridge. The term “nodule” is usually used to refer to a ridge of skin that resembles a papule but has a white dome shape. Colloquially, papules, pustules or nodules can be called “pimples” or “acne”. The term “cyst” usually refers to an abnormal membrane sac containing a liquid or semi-liquid substance containing white blood cells, dead cells and bacteria. The cyst is painful and can extend deep into the skin.

  In dermatology and dermatological and cosmetic practice, acne depends on one or more classification boundaries, for example, depending on the predominant symptom type, severity of symptoms, or dominant localization, It can be classified or sorted into one or more types or categories. It should be understood that classifying acne into one or more subtypes does not mean limiting the characteristics of the classified symptoms to symptoms associated with a particular type.

  Acne vulgaris is a common form of acne characterized by the appearance of several types of lesions that may appear together or separately. Individual acne lesions usually last less than 2 weeks, but deeper papules and nodules can last for a month. Acne vulgaris usually affects adolescents but can also appear, persist or become severe in adults. Acne vulgaris can occur on the face, chest, back, and sometimes even wider areas.

  Acne can be mild, moderate or severe depending on the severity. Mild acne is generally differentiated by its appearance with black and white acne, but can also include papules and pustules. Moderate acne is generally characterized by the appearance of a more painful and deep inflammatory lesion, which can cause scarring. Severe acne is characterized by the appearance of deep-seated inflammatory lesions, including cysts and nodules that can be painful and scarring. Confluent acne is a type of acne characterized by highly inflammatory cysts that communicate with the abscess and perforated sinus tract beneath the skin.

  Several other skin conditions that exhibit acne-like symptoms that can be treated by the compositions and methods described herein are described below. Facial pyoderma, also known as electric shock, is a symptom that appears in women and is characterized by the sudden appearance of inflammatory cysts and nodules localized on the face. Rosacea, sometimes called rosacea acne, is a symptom that can affect both the skin and the eyes and is characterized by redness, aneurysms, pimples, and thickened skin of the nose at an advanced stage . Some classification systems consider rosacea and acne as separate symptoms. Rashiness usually occurs on the face but often includes the neck and upper chest. Mild eye (vision) involvement occurs in more than 50 percent of people with rosacea. Perioral dermatitis is characterized by scaling with very small papules, pustules, erythema and strong itching. It is usually localized in the area around the mouth and jaw, or extends to the eyelids and forehead. Gram-negative folliculitis is a bacterial infection characterized by the appearance of pustules and cysts and can occur as a complication resulting from long-term antimicrobial treatment of acne vulgaris.

  As used herein, the term “treatment” or “treating” with respect to skin symptoms usually means “giving a good effect on skin symptoms” and alleviation of at least one symptom of skin symptoms. , Including reducing the severity of skin symptoms or delaying, preventing or suppressing the progression of skin symptoms. Treatment need not mean that the symptoms are completely cured. Compositions or products useful for the treatment of skin symptoms, or methods of treating skin symptoms, simply reduce the severity of the skin symptoms, reduce the severity of the associated symptoms, or improve the quality of life of the patient. Need only to delay, prevent or suppress the onset of skin symptoms.

Formulation In one embodiment, a composition comprising dapsone, a first solubilizer that is diethylene glycol monoethyl ether, an optional at least one second solubilizer, a polymeric viscosity improver, and water. Dapsone is about 5% to about 10%, about 1% to about 10%, about 3% to about 10%, about 3% to about 8%, about 4% by weight. Such compositions are provided that are present at a concentration of about 6% by weight, or about 5%. In certain embodiments, dapsone is 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0% by weight percent in the composition. , 8.5%, 9.0%, 9.5% or 10.0%.

  In some embodiments, the polymeric viscosity improver is an acrylamide / acryloyldimethyltaurine sodium copolymer and further comprises isohexadecane, water, and polysorbate 80. In some embodiments, the polymeric viscosity improver is present at a concentration of about 2% to about 6% by weight. In some embodiments, the polymeric viscosity improver is present at a concentration of about 3% to about 5% by weight. In some embodiments, the polymeric viscosity improver is present in the composition at about 4% by weight. An example of a commercially available polymeric viscosity improver comprising an acrylamide / acryloyldimethyltaurine sodium copolymer is Sepineo P600, the entire MSDS of which is incorporated by reference.

  In some embodiments, diethylene glycol monoethyl ether is present at a concentration of about 25% to about 40% by weight. In some embodiments, diethylene glycol monoethyl ether is present at a concentration of about 30% to about 40% by weight. In some embodiments, diethylene glycol monoethyl ether is present at a concentration of about 35% to about 40% by weight.

  In some embodiments, the diethylene glycol monoethyl ether is present at a concentration of about 10% to about 40%, about 20% to about 30%, or about 25% by weight. In some embodiments, diethylene glycol monoethyl ether is present at a concentration of about 30% by weight.

  In some embodiments, the second solubilizer is selected from alcohols, glycols, esters, ethers or silicones. Examples of such second solubilizer include, but are not limited to, PEG400, lactic acid, dimethylisosorbide, propylene glycol, propylene carbonate, hexylene glycol, isostearyl alcohol, benzyl alcohol, diethyl sebacate and ethanol.

  In certain embodiments, the second solubilizer is propylene glycol. In some embodiments, propylene glycol is present at a concentration of about 2% to 8% by weight. In some embodiments, propylene glycol is present at a concentration of about 3% to 7% by weight. In some embodiments, propylene glycol is present in the composition at about 5% by weight.

  In certain embodiments, the second solubilizer is propylene carbonate. In some embodiments, propylene carbonate is present at a concentration of about 2% to 8% by weight. In some embodiments, propylene carbonate is present at a concentration of about 3% to 7% by weight. In some embodiments, propylene carbonate is present in the composition at about 5% by weight.

  In certain embodiments, the second solubilizer is ethanol. In some embodiments, ethanol is present at a concentration of about 1% to 5% by weight. In some embodiments, ethanol is present at a concentration of about 2% to 4% by weight. In some embodiments, ethanol is present in the composition at about 3% by weight.

  In some embodiments, the composition further comprises methyl paraben.

  In other embodiments, the composition further comprises carbomer homopolymer type C. In some embodiments, the carbomer homopolymer Form C is present at a concentration of about 0.7% to about 1.5% by weight. In other embodiments, the carbomer homopolymer Form C is present at a concentration of about 0.85% to about 1.0% by weight.

  In some embodiments, the composition further comprises a neutralizing agent. In certain embodiments, the neutralizing agent is an ionic buffer or an amine buffer. In certain embodiments, the neutralizing agent is sodium hydroxide or triethanolamine. The use of a neutralizing agent typically brings the pH of the composition to 5.5-6.5.

  In some embodiments, the composition further comprises a chelating agent. In some embodiments, the chelator is ethylenediaminetetraacetic acid (EDTA). EDTA is typically present in the composition from about 0.02% to about 0.04% by weight. In certain embodiments, EDTA is present in the composition at about 0.03% by weight.

  The compositions described herein are typically in the form of a gel, emulsion, cream, liquid, paste, lotion, nanoemulsion, microemulsion, inverse emulsion or liposomal cream. For example, in one embodiment, the composition can be 7.5 wt% dapsone gel in a pump dispenser.

Methods of Treatment According to some embodiments, methods are provided for treating acne vulgaris using the dapsone formulations described herein.

  In one embodiment, a patient with acne vulgaris can implement a treatment plan for a period of time effective to improve acne vulgaris. The plan can include applying the dapsone gel formulation described herein to the patient's face once a day. In some embodiments, the plan can include applying the 7.5 wt% dapsone gel formulation described herein to the patient's face once a day. In some embodiments, the program includes about 7.5% by weight dapsone, about 40% by weight diethylene glycol monoethyl ether, and about 4% acrylamide / acryloyldimethyltaurine sodium copolymer thickener. Including the gel formulation described herein comprising application to the patient's face once a day.

  According to some embodiments, the treatment plan can be performed frequently enough over a period of time effective to improve acne vulgaris. In some embodiments, the treatment plan can be performed only once a day. If the treatment plan is performed once a day, it can be performed at various times, such as at night or in the morning.

  In some embodiments, the treatment plan can be implemented over a treatment duration effective to improve acne vulgaris. In some embodiments, a treatment duration effective to improve acne vulgaris can be about 12 weeks. Effective treatment durations for improving acne vulgaris can be about 4 weeks, about 8 weeks, about 10 weeks, and the like. According to some embodiments, the treatment duration effective to improve acne vulgaris can be about 12 weeks or more, about 10 weeks or more, about 8 weeks or more, about 4 weeks or more, etc. . In some embodiments, a treatment duration effective to ameliorate acne vulgaris can range from about 2 weeks to about 12 weeks. In some embodiments, the treatment duration effective to ameliorate acne vulgaris can range from about 4 weeks to about 12 weeks. In some embodiments, the treatment duration effective to improve acne vulgaris can range from about 8 weeks to about 12 weeks. According to some embodiments, the treatment duration effective to improve acne vulgaris can be determined by the patient's physician.

  In some embodiments, improving acne vulgaris can include reducing the severity of acne vulgaris in the patient. For example, the improvement of acne vulgaris reduces, for example, the number of inflammatory and / or non-inflammatory foci, comedones, papules / pustules or nodular cystic foci present on the face of patients with acne vulgaris Can be included. In some embodiments, there may be an improvement when the patient's nodule changes from inflammatory to non-inflammatory. According to some embodiments, the improvement of acne vulgaris eliminates the severity of acne vulgaris as assessed by a physician and / or self-evaluated by the patient (eg, there is no evidence of acne vulgaris) Or almost none) (eg, rare non-inflammatory papules with rare non-inflammatory lesions).

  A topical gel formulation can be provided as described above. For example, in one embodiment, a topical gel formulation is provided comprising dapsone with dapsone present in the topical gel formulation in an amount of about 7.5% by weight, based on the total weight of the topical gel formulation. Can.

  In some embodiments, the topical dapsone gel formulation can be applied to the face of a patient with acne vulgaris. According to some embodiments, the topical dapsone gel formulation can be applied to the entire patient's face. After the topical dapsone gel formulation is applied to the patient's face, the topical dapsone gel formulation can be rubbed over the patient's face. In some embodiments, the topical dapsone gel formulation can be rubbed over the patient's face except for the eye, mouth, and the eye area and / or the area surrounding the mouth area. In some embodiments, the topical dapsone gel formulation may be applied only to facial areas exhibiting symptoms of acne.

  According to some embodiments, the topical dapsone gel formulation can remain on the face for an extended period of time after it is applied. In such an embodiment, the patient should not take a bath or shower for that long period. In some embodiments, the extended period can be about 8 hours or more, about 6 hours or more, about 4 hours or more, and the like.

Post-inflammatory pigmentation In some embodiments, methods of treating post-inflammatory pigmentation using the dapsone formulations described herein are provided. Post-inflammatory pigmentation (PIH) is a condition in which increased skin pigmentation or inflammation causes increased pigment production. PIH occurs in dark-skinned individuals (eg, Fitzpatrick type 5 or 6) and can be difficult to treat. The most common cause of PIH is acne, but it can also be caused by psoriasis, burns or injuries. In some embodiments, the PIH being treated is caused by acne vulgaris.

  In one embodiment, patients with PIH can implement a treatment plan for a period of time effective to improve PIH. The plan can include applying the dapsone gel formulation described herein to the patient's face once a day. In some embodiments, the plan can include applying the 7.5 wt% dapsone gel formulation described herein to the patient's face once a day. In some embodiments, the program includes about 7.5% by weight dapsone, about 40% by weight diethylene glycol monoethyl ether, and about 4% acrylamide / acryloyldimethyltaurine sodium copolymer thickener. Including the gel formulation described herein comprising application to the patient's face once a day.

  According to some embodiments, the treatment plan can be performed frequently enough over a period of time effective to improve the patient's post-inflammatory pigmentation. In some embodiments, the treatment plan can be performed only once a day. If the treatment plan is performed once a day, it can be performed at various times, such as at night or in the morning.

  In some embodiments, the treatment plan can be implemented over a treatment duration effective to improve PIH. In some embodiments, the treatment duration effective to improve PIH can be about 12 weeks. Effective treatment durations for improving PIH can be about 4 weeks, about 8 weeks, about 10 weeks, and the like. According to some embodiments, a treatment duration effective to improve PIH can be about 12 weeks or more, about 10 weeks or more, about 8 weeks or more, about 4 weeks or more, and the like. In some embodiments, the treatment duration effective to improve PIH can range from about 2 weeks to about 12 weeks. In some embodiments, the treatment duration effective to improve PIH can range from about 4 weeks to about 12 weeks. In some embodiments, the treatment duration effective to improve PIH can range from about 8 weeks to about 12 weeks. According to some embodiments, a treatment duration effective to improve PIH can be determined by the patient's physician.

  In some embodiments, an improvement in PIH can include a reduction in the severity of the patient's PIH. For example, improving PIH can include, for example, reducing the number of dark spots and / or reducing dark spots present on the face of a patient having PIH. In some embodiments, the reduction in PIH can include the complete elimination of dark spots on the patient's face.

  In some embodiments, the treatment method can be effective to treat patients with both acne vulgaris and PIH. For example, patients with acne vulgaris may be able to treat acne using the formulations and methods described above, and thus treat PIH resulting from acne vulgaris with the same formulations and methods. Would be able to.

Embodiments The following exemplary dapsone formulation embodiments are specifically contemplated herein.
Embodiment 1. FIG. A composition comprising dapsone, a first solubilizer that is diethylene glycol monoethyl ether, an optional at least one second solubilizer, a polymer viscosity improver, and water. The composition is present in the composition at a concentration of about 3% to about 10% by weight.
Embodiment 2. FIG. The composition of embodiment 1, wherein the diethylene glycol monoethyl ether is present at a concentration of about 10% to about 40% by weight.
Embodiment 3. FIG. The composition of embodiment 1, wherein the diethylene glycol monoethyl ether is present at a concentration of about 20% to about 30% by weight.
Embodiment 4 FIG. The composition of embodiment 1, wherein the diethylene glycol monoethyl ether is present in the composition at a concentration of about 25% by weight.
Embodiment 5. FIG. The composition of embodiment 1, wherein the second solubilizer is selected from alcohols, glycols, esters or ethers.
Embodiment 6. FIG. The composition according to embodiment 1, wherein the second solubilizer is PEG400, lactic acid, dimethylisosorbide, propylene glycol, propylene carbonate, hexylene glycol, isostearyl alcohol, diethyl sebacate or ethanol.
Embodiment 7. FIG. Embodiment 7. The composition according to embodiment 6, wherein the second solubilizer is propylene glycol.
Embodiment 8. FIG. The composition of embodiment 7, wherein the propylene glycol is present in the composition at a concentration of about 5% by weight.
Embodiment 9. FIG. Embodiment 7. The composition according to embodiment 6, wherein the second solubilizer is propylene carbonate.
Embodiment 10 FIG. The composition of embodiment 9, wherein the propylene carbonate is present in the composition at a concentration of about 5% by weight.
Embodiment 11. FIG. Embodiment 7. The composition according to embodiment 6, wherein the second solubilizer is ethanol.
Embodiment 12 FIG. Embodiment 12. The composition of embodiment 11 wherein the ethanol is present in the composition at a concentration of about 3% by weight.
Embodiment 13. FIG. The composition of embodiment 1, wherein the polymeric viscosity improver comprises an acrylamide / acryloyldimethyltaurine sodium copolymer.
Embodiment 14 FIG. The composition of embodiment 1, wherein the polymeric viscosity improver is present at a concentration of about 2 wt% to about 6 wt%.
Embodiment 15. FIG. The composition of embodiment 1, wherein the polymeric viscosity improver is present at a concentration of about 4% by weight.
Embodiment 16. FIG. The composition of embodiment 1, further comprising methylparaben.
Embodiment 17. FIG. The composition of embodiment 1, further comprising a carbomer interpolymer type A, a carbomer interpolymer type B, or a carbomer homopolymer type C.
Embodiment 18. FIG. Embodiment 18. The composition of embodiment 17, wherein the carbomer homopolymer Form C is present at a concentration of about 0.7% to about 1.5% by weight.
Embodiment 19. FIG. Embodiment 18. The composition of embodiment 17, wherein the carbomer homopolymer Form C is present at a concentration of about 0.85 wt% to about 1.5 wt%.
Embodiment 20. FIG. Embodiment 18. The composition of embodiment 17, wherein the carbomer interpolymer Form A is present at a concentration of about 1% to 2% by weight.
Embodiment 21. FIG. Embodiment 18. The composition of embodiment 17, wherein the carbomer interpolymer Form B is present at a concentration of about 0.1% to 0.5% by weight.
Embodiment 22. FIG. The composition of embodiment 1, further comprising a neutralizing agent.
Embodiment 23. FIG. Embodiment 23. The composition of embodiment 22 wherein the neutralizing agent is NaOH or triethanolamine.
Embodiment 24. FIG. The composition of embodiment 1, further comprising a chelating agent.
Embodiment 25. FIG. Embodiment 25. The composition of embodiment 24 wherein the chelator is ethylenediaminetetraacetic acid.
Embodiment 26. FIG. 26. The composition of embodiment 25, wherein the ethylenediaminetetraacetic acid is present at a concentration of about 0.02% to about 0.04% by weight.
Embodiment 27. FIG. 26. The composition of embodiment 25, wherein ethylenediaminetetraacetic acid is present in the composition at about 0.03% by weight.
Embodiment 28. FIG. The composition of embodiment 1, wherein the composition is in the form of a gel, suspension, emulsion, cream, liquid, paste, lotion, nanoemulsion, microemulsion, inverse emulsion or liposomal cream.
Embodiment 29. FIG. A method of treating a dermatological condition comprising administering to a subject in need of treatment of a dermatological condition a therapeutically effective amount of the composition of embodiment 1.
Embodiment 30. FIG. The symptoms include acne vulgaris, rosacea, atopic dermatitis, treatment of chronic wounds, bed sores, pore keratosis, sebaceous cysts, inflammatory skin diseases, post-inflammatory pigmentation, eczema, dryness, pruritus 30. The method of embodiment 29, wherein the disease is lichen planus, nodular rash, dermatitis, eczema or rash.
Embodiment 31. FIG. The method of embodiment 30, wherein the symptom is acne vulgaris.
Embodiment 32. FIG. Embodiment 32. The composition of embodiment 1, 2, 3, 4, 30 or 31 wherein the second solubilizer is selected from alcohols, glycols, esters or ethers.
Embodiment 33. FIG. Embodiments 1, 2, 3, 4, 30, 31 wherein the second solubilizer is PEG400, lactic acid, dimethylisosorbide, propylene glycol, propylene carbonate, hexylene glycol, isostearyl alcohol, diethyl sebacate or ethanol Or the composition according to 32.
Embodiment 34. FIG. 34. The composition of embodiment 33, wherein the second solubilizer is propylene glycol.
Embodiment 35. FIG. 35. The composition of embodiment 34, wherein the propylene glycol is present in the composition at a concentration of about 5% by weight.
Embodiment 36. FIG. Embodiment 34. The composition of embodiment 33, wherein the second solubilizer is propylene carbonate.
Embodiment 37. FIG. 37. The composition of embodiment 36, wherein the propylene carbonate is present in the composition at a concentration of about 5% by weight.
Embodiment 38. FIG. Embodiment 34. The composition of embodiment 33, wherein the second solubilizer is ethanol.
Embodiment 39. FIG. 39. The composition of embodiment 38, wherein the ethanol is present in the composition at a concentration of about 3% by weight.
Embodiment 40. FIG. Embodiment 1, 2, 3, 4, 30, 31, 32, 33, 34, 35, 36, 37, 38 or 39, wherein the polymeric viscosity improver comprises an acrylamide / acryloyldimethyltaurine sodium copolymer. Composition.
Embodiment 41. FIG. Embodiments 1, 2, 3, 4, 30, 31, 32, 33, 34, 35, 36, 37, 38, wherein the polymeric viscosity improver is present in a concentration of about 2 wt% to about 6 wt%. 41. The composition according to 39 or 40.
Embodiment 42. FIG. 42. The composition of embodiment 41, wherein the polymeric viscosity improver is present at a concentration of about 4% by weight.
Embodiment 43. FIG. The composition of embodiment 1, 2, 3, 4, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 or 42, further comprising methyl paraben.
Embodiment 44. FIG. Embodiments 1, 2, 3, 4, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, further comprising carbomer interpolymer type A, carbomer interpolymer type B, or carbomer homopolymer type C 40, 41, 42 or 43.
Embodiment 45. FIG. 45. The composition of embodiment 44, wherein the carbomer homopolymer Form C is present at a concentration of about 0.7% to about 1.5% by weight.
Embodiment 46. FIG. 45. The composition of embodiment 44, wherein the carbomer homopolymer Form C is present at a concentration of about 0.85% to about 1.5% by weight.
Embodiment 47. 45. The composition of embodiment 44, wherein the carbomer interpolymer Form A is present at a concentration of about 1% to 2% by weight.
Embodiment 48. FIG. 45. The composition of embodiment 44, wherein the carbomer interpolymer Form B is present at a concentration of about 0.1% to 0.5% by weight.
Embodiment 49. Embodiments 1, 2, 3, 4, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, further comprising a neutralizing agent 47, 48 or 48.
Embodiment 50. FIG. 50. The composition of embodiment 49, wherein the neutralizing agent is NaOH or triethanolamine.
Embodiment 51. FIG. Embodiments 1, 2, 3, 4, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, further comprising a chelating agent 51. The composition according to 47, 48, 49 or 50.
Embodiment 52. FIG. 52. The composition of embodiment 51, wherein the chelator is ethylenediaminetetraacetic acid.
Embodiment 53. FIG. 53. The composition of embodiment 52, wherein the ethylenediaminetetraacetic acid is present at a concentration of about 0.02% to about 0.04% by weight.
Embodiment 54. FIG. 53. The composition of embodiment 52, wherein the ethylenediaminetetraacetic acid is present in the composition at about 0.03% by weight.
Embodiment 55. FIG. Embodiments 1, 2, 3, 4, 30, 31, wherein the composition is in the form of a gel, suspension, emulsion, cream, liquid, paste, lotion, nanoemulsion, microemulsion, inverse emulsion or liposome cream 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 or 54 .
Embodiment 56. FIG. A therapeutically effective amount of Embodiment 1, 2, 3, 4, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, to a subject in need of treatment for dermatological symptoms 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55. A method for treating a dermatological condition.
Embodiment 57. FIG. The symptoms include acne vulgaris, rosacea, atopic dermatitis, treatment of chronic wounds, bed sores, pore keratosis, sebaceous cysts, inflammatory skin diseases, post-inflammatory pigmentation, eczema, dryness, pruritus 57. The method of embodiment 56, wherein the disease is lichen planus, nodular rash, dermatitis, eczema or rash.
Embodiment 58. FIG. 57. The method of embodiment 56, wherein the symptom is acne vulgaris.

  The following examples are intended only to illustrate some embodiments and are not to be construed as limiting the claims in any way.

Example 1
Table 1 lists two formulations (containing equivalent levels of diethylene glycol monoethyl ether) that show the effect of the acrylamide / acryloyldimethyltaurine sodium copolymer thickener on the dapsone particle size.

Example 2
Antioxidants and chelating agents such as sodium pyrosulfite, citric acid and EDTA were added to the formulation to facilitate slowing down or completely stopping any impurity formation. Table 2 shows the composition of the formulations tested. Formulation A7 containing sodium pyrosulfite minimizes the yellow intensity caused by the increased solubility of dapsone in diethylene glycol monoethyl ether and maintains its low color intensity over time in accelerated conditions (400 ° C.). .

Example 3
Additional exemplary compositions contemplated for the applications described herein are shown in Table 3 below.

Example 4
Additional exemplary compositions contemplated for the applications described herein are shown in Table 4 below.

Example 5
Clinical studies Two phase 3 clinical studies investigated the safety and efficacy of using 7.5 wt% Dapsone gel in the treatment of acne vulgaris compared to vehicle.

The formulations used in the study included the formulation components listed below.

  A total of 4340 patients participated in the Phase 3 study. Patients participating in the study were over 12 years old and had 20-50 inflammatory lesions and about 30-100 non-inflammatory lesions. The study coordinator randomly assigned patients to either of the two treatment groups in a 1: 1 ratio. In the first group, patients received a topical dapsone gel formulation containing 7.5 wt% dapsone once a day, over the entire face. In the second group, the patient received the vehicle formulation once a day. The patient was treated for 12 weeks. Patients were evaluated by physicians at 0, 1, 2, 4, 8 and 12 weeks for reduction of inflammatory and non-inflammatory lesions and adverse events throughout the study. Combining the results of the two studies, FIG.

  Surprisingly, the average reduction rate of all lesions was statistically significantly better than the vehicle from week 4 to week 12. Both inflammatory and non-inflammatory were significantly reduced. Specifically, the mean reduction rate of all lesions in patients receiving a topical dapsone gel formulation containing 7.5% by weight dapsone once daily on the face is -31.6% at 4 weeks, It was -40.9% at 8 weeks and -49.3% at 12 weeks. At 12 weeks, the inflammatory lesions are reduced by 15.8 lesions (54.6%; n = 2162), whereas the vehicle is reduced by 13.9 lesions (48.1%; n = 2178) Also, non-inflammatory lesions decreased by 20.7 lesions (45.1%), whereas vehicle decreased by 18.0 lesions (39.4%). The patient's overall acne score “GAAS” success rate was 29.8% (n = 2162) versus 21.1% (n = 2178) in the vehicle.

  Patients were further evaluated for erythema, scaling, dryness and tingling / burning throughout the study. A chart showing the incidence of local skin irritation in patients whose stimulation points are higher than the baseline is shown in FIG. Surprisingly, the amount and severity of erythema, scaling, dryness and tingling / burning was reduced over the treatment period (baseline to 12 weeks of final treatment). Furthermore, the formulation was very well tolerated during the study. Less than 1% of all patients suffered redness, dryness and peeling of the treated skin.

  Although the improvement in acne severity was significant in all age, gender and race subgroups, the improvement was even greater in adults than adolescents and in women rather than men.

  During the same study, a statistically significant resolution of post-inflammatory pigmentation in patients was also revealed. Specifically, dark skin patients (Fitzpatrick type 5 or 6) experienced accelerated resolution of post-inflammatory pigmentation caused by acne. There was a decrease in the number of dark spots, and a significant number of patients reported the disappearance of dark spots at 12 weeks of treatment.

  Although several embodiments of this have been described with respect to these specific examples, it will be understood that other modifications and variations are possible without departing from the spirit of the invention. Each and every reference identified herein is incorporated by reference in its entirety.

Axon® gel 7.5% formulation information is attached hereto, which is one embodiment of the formulations and methods of treatment described herein.

Complete Prescribing Information 1 Efficacy and Usage Axon® (Dapson) Gel 7.5% is indicated for the local treatment of acne vulgaris in patients over 12 years old.
2 Dose and administration For topical use only. Not for oral, ophthalmic or intravaginal use.
After gently washing the skin and gently pressing it dry, a bean-sized amount of Axon Gel 7.5% is applied to the entire face once a day as a thin film. In addition, a thin film may be applied to other affected areas once a day. Gently thoroughly rub the Axon gel 7.5%.
If there is no improvement after 12 weeks, treatment with Axon Gel 7.5% should be reviewed (2).
3 Dosage form and content Gel, 7.5%. One gram of Akzone gel 7.5% contains 75 mg of dapsone in an off-white to yellow gel containing suspended particles.
4 Contraindications None.
5 Warnings and precautions 5.1 Hematological effects Methemoglobinemia A case of methemoglobinemia with concomitant hospitalization was reported post-marketing in relation to twice daily treatment with dapsone gel 5%. It was. Patients with glucose-6-phosphatase dehydrogenase deficiency or congenital or idiopathic methemoglobinemia are more susceptible to drug-induced methemoglobinemia. Avoid the use of Axon Gel 7.5% for those patients with congenital or idiopathic methemoglobinemia.
Signs and symptoms of methemoglobinemia can be delayed for several hours after exposure. Early signs and symptoms of methemoglobinemia are characterized by the bluish dark gray cyanosis found, for example, in the buccal mucosa, lips and nail bed. In the case of cyanosis, advise the patient to discontinue Akzon Gel 7.5% and see a doctor immediately.
Dapsone can cause elevated levels of methemoglobin, especially in conjunction with methemoglobin-inducing drugs [see Drug Interactions (7.4)].
Hemolysis Treatment with oral dapsone resulted in dose-related hemolysis and hemolytic anemia. Glucose-6-phosphatase dehydrogenase (G6PD) deficiency is more prone to hemolysis with the use of certain drugs. G6PD deficiency is most prevalent in ancestral populations in Africa, South Asia, the Middle East and the Mediterranean.
Clinical trials have not demonstrated clinically relevant hemolysis or hemolytic anemia in subjects treated with topical dapsone. Several subjects with G6PD deficiency using dapsone gel 5% twice daily showed clinical changes suggesting hemolysis [see Use in Specific Populations (8.6)] .
If signs and symptoms suggest hemolytic anemia occur, discontinue Axon Gel 7.5%. Avoid use of Axon Gel 7.5% in patients taking oral dapsone or antimalarial drugs because of potential hemolytic reactions. Combination of Axon Gel 7.5% with trimethoprim / sulfamethoxazole (TMP / SMX) may increase the possibility of hemolysis in patients with G6PD deficiency [see Drug Interactions (7.1) about].
5.2 Peripheral neuropathy Peripheral neuropathy (loss of motility and weakness) has been reported for treatment with oral dapsone. There were no cases of peripheral neuropathy in clinical trials for treatment with topical dapsone.
5.3 Skin reactions Skin reactions (toxic epidermal necrosis, erythema multiforme, measles-like and scarlet fever-like reactions, bullous and exfoliative dermatitis, nodular erythema and urticaria) with regard to treatment with oral dapsone It has been reported. In clinical trials for treatment with topical dapsone, these types of skin reactions were not observed.
6 Adverse reactions 6.1 Knowledge of clinical studies Because clinical trials are conducted under a wide range of symptoms, the rate of adverse reactions observed in a clinical study of a drug cannot be directly compared with the rate in a clinical study of another drug. And may not reflect the actual rate allowed.
In two comparative clinical trials, a total of 2161 subjects were treated with Axon gel 7.5% for 12 weeks. The age range of the population was 12-63 years, 56% were women and 58% were white. The adverse drug reactions reported in at least 0.9% of subjects treated with Axon gel 7.5% are shown in Table 1 below.
6.2 Findings from oral use of dapsone Severe adverse reactions were not observed in clinical trials using topical dapsone, but oral use of dapsone resulted in agranulocytosis, hemolytic anemia, peripheral Neuropathy (loss of motility and muscle weakness) and skin reactions (toxic epidermal necrosis, erythema multiforme, measles and scarlet fever-like reactions, bullous and exfoliative dermatitis, erythema nodosum and urticaria) Have been reported.
6.3 Post-marketing findings The following adverse reactions were identified during use after approval of topical dapsone. Because these responses are voluntarily reported from an uncertain size population, it is not always possible to reliably estimate their frequency or to establish a causal relationship with drug exposure.
Methemoglobinemia was identified during the post-marketing use of topical dapsone [see warnings and precautions (5.1)].
7 Drug interaction No formal drug-drug interaction studies were performed on Axon gel 7.5%.
7.1 Trimethoprim / sulfamethoxazole In drug-drug interaction studies, the effect of using 5% dapsone gel in combination with double strength (160 mg / 800 mg) trimethoprim / sulfamethoxazole (TMP / SMX) It was evaluated. During co-administration, systemic levels of TMP and SMX were essentially unchanged, but levels of dapsone and its metabolites were increased in the presence of TMP / SMX. Systemic exposure with Axon Gel 7.5% is expected to be about 1% of that with a 100 mg oral dose, even when coadministered with TMP / SMX.
7.2 Topical benzoyl peroxide Topical application of benzoyl peroxide following dapsone gel in patients with acne vulgaris can cause temporary and local yellow or orange discoloration of the skin and facial hair .
7.3 Drug Interactions with Oral Dapsone Certain concomitant medications (eg, rifampin, anticonvulsants, St. John's wort) can increase the formation of dapsone hydroxylamine, a hemolysis-related metabolite of dapsone. Regarding treatment with oral dapsone, it has been indicated that folic acid antagonists, such as pyrimethamine, have increased the likelihood of a hematological response.
7.4 Simultaneous use with drugs that induce methemoglobinemia Axon gel 7.5% and drugs that induce methemoglobinemia (eg sulfonamides, acetaminophen, acetanilide, aniline dyes, benzocaine, chloroquine, dapsone, Naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, parakin, paraaminosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine and quinine) may increase the risk of developing methemoglobinemia [Warning And see Precautions for Use (5.1)].
8 Use in specific populations 8.1 Pregnancy Teratogenic effects: Fetal risk classification C
There are no adequate and adequate controlled studies in pregnant women. Akzon gel 7.5% should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Dapsone was approximately 1400 and 425 times the total systemic exposure associated with 75 mg / kg / day and 150 mg / kg / day (maximum recommended human dose (MRHD) of axon gel 7.5% based on AUC comparison, respectively) during organogenesis ) Has been shown to have a fetal killing effect in rats and rabbits, respectively. These effects were probably secondary to maternal toxicity.
8.3 Lactating mothers Systemic absorption of dapsone after topical application of Axon Gel 7.5% is minimal compared to oral dapsone administration, but dapsone is transferred into human milk It has been known. Because oral dapsone has the potential to cause adverse reactions in the suckling fetus, it must be decided whether to stop breastfeeding or to stop Axon Gel 7.5% taking into account the importance of the drug to the mother .
8.4 Use in children In clinical trials, safety and usefulness in 1066 subjects aged 12 to 17 years treated with Axon Gel 7.5% was evaluated. The safety properties of Axon Gel 7.5% were similar to the vehicle control group. The safety and efficacy of Axon Gel 7.5% has not been established in pediatric patients under 12 years of age.
8.5 Elderly use Axon gel 7.5% clinical trials did not include a sufficient number of subjects over 65 years old and whether they responded differently from younger subjects It was judged.
8.6 Glucose-6-phosphatase dehydrogenase (G6PD) deficiency Individuals with glucose-6-phosphatase dehydrogenase (G6PD) deficiency may be more prone to methemoglobinemia and hemolysis [Warning and See Precautions for Use (5.1)].
Axon gel 5% and vehicle were evaluated in a randomized, double-blind cross-over clinical study of 64 subjects with G6PD deficiency and acne vulgaris. Subjects were black (88%), Asian (6%), Hispanic (2%) or other racial origin (5%). Blood samples were taken at baseline, 2 weeks and 12 weeks during both treatments with vehicle and Akson gel 5%. Several of these subjects exhibited clinical changes suggesting hemolysis, but clinically significant hemolytic anemia was not demonstrated in this study [Warning and Precautions (5.1) checking].
11 Description Axon (Dapson) gel 7.5% contains dapsone, a sulfone, in an aqueous gel matrix for topical dermatological use. Axon gel 7.5% is an off-white to yellow gel containing suspended particles. Chemically, Dapsone has the empirical formula C ₁₂ H ₁₂ N ₂ O ₂ S. It is a white or slightly yellowish white crystalline powder with a molecular weight of 248.30. Dapsone's chemical name is 4-[(4-aminobenzene) sulfonyl] aniline, and its structural formula is as follows.
One gram of Akzone gel 7.5% contains 75 mg of USP dapsone in a gel consisting of diethylene glycol monoethyl ether, methyl paraben, acrylamide / acryloyldimethyltaurine sodium copolymer, isohexadecane, polysorbate 80 and purified water.
12 Clinical Pharmacology 12.1 Mechanism of Action The mechanism of action of dapsone gel in the treatment of acne vulgaris is unknown.
12.3 Pharmacokinetics In a pharmacokinetic study, male and female subjects (N = 19) over 16 years of age with acne vulgaris faced 2 grams of Akzone Gel 7.5% once daily for 28 days. Received locally on the upper chest, upper back and shoulders. Dapsone reached steady state within 7 days of dosing. On day 28, the mean Dapsone maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC _0-24h ) from 0 to 24 hours after dosing were 13.0 ± 6.8 ng / mL and 282 ± 146 ng · h / mL. Systemic exposure with Axon Gel 7.5% is expected to be about 1% of that with an oral dose of 100 mg.
A long-term safety study was not performed on Akson gel 7.5%, but in a long-term clinical study of treatment with dapsone gel 5% (twice daily), blood was routinely collected until approximately month 12 in approximately 500 subjects. Samples were taken to determine systemic exposure to dapsone and its metabolites. Based on measurable dapsone concentrations from 408 subjects (M = 192, F = 216) obtained at 3 months, neither gender nor race appears to affect the pharmacokinetics of dapsone. It was. Similarly, dapsone exposure was approximately the same in the 12-15 year old age group (N = 155) and in those over 16 years old (N = 253). These subjects have not been shown to increase systemic exposure to dapsone over the study year.
12.4 Microbiology In vivo activity: Axon gel 7.5% No microbiology or immunology studies were conducted during clinical studies.
Drug resistance: No dapsone resistance studies were conducted during the dapsone gel clinical study. Because no such research has been done, the use of whether or not dapsone has reduced the sensitivity of Propionibacterium acnes, an organism related to acne, or other antimicrobial agents that can be used to treat acne There is no data available. Therapeutic resistance to dapsone has been reported in Mycobacterium leprae when treating patients with oral dapsone.
13 Nonclinical toxicology 13.1 Carcinogenicity, mutagenicity, fertility disorder Up to 15 mg / kg / day (approx. 340 times systemic exposure associated with MRHD of Axon Gel 7.5% based on AUC comparison) It was not carcinogenic to rats when administered orally at lifetime dose levels.
Tg. A skin study of topical application of dapsone gel to AC transgenic mice for approximately 26 weeks provided no evidence for the potential to induce carcinogenicity. 3%, 5% and 10% dapsone concentrations were evaluated; 3% of material was determined to be the maximum tolerated dose.
Topical gels containing dapsone at concentrations up to 5% did not increase the rate of UV-induced skin tumor formation when topically applied to hairless mice in a 12 month photocarcinogenicity study.
Dapson typhimurium and E. coli. Bacterial reverse mutation test using E. coli (Ames test) was not mutagenic with or without metabolic activation and was negative in the micronucleus test performed in mice. Dapsone increased both numerical and structural abnormalities in chromosomal aberration tests performed on Chinese hamster ovary (CHO) cells.
The effect of dapsone on fertility and general reproductive performance was evaluated in male and female rats after oral (gavage) dosing. Dapsone reduced sperm motility at doses of 3 mg / kg / day and higher (approximately 22 times the systemic exposure associated with MRHD of Axon gel 7.5% based on AUC comparison). The average number of embryo implantation and surviving embryos was unmatched with males dosed with 12 mg / kg / day or higher (approximately 187 times the systemic exposure associated with MRHD of Axon gel 7.5% based on AUC comparison). In treated females, there was a significant decrease, possibly due to a decrease in the number or effectiveness of sperm, indicating impaired fertility. Dapsone did not affect male fertility at doses of 2 mg / kg / day or less (approximately 15 times the systemic exposure associated with MRHD of Axon gel 7.5% based on AUC comparison). Dapsone is administered to female rats at a dose of 75 mg / kg / day (approximately 1400 times systemic exposure associated with Akzon gel 7.5% MRHD based on AUC comparison) for 15 days before mating and 17 days after mating. In this case, the average number of implantations was decreased, the average early absorption rate was increased, and the average number of litters was decreased. These effects were probably secondary to maternal toxicity.
In a study in which dapsone was orally administered to female rats starting on day 7 of conception and continuing daily until day 27 after parturition, regarding perinatal / postnatal offspring development and effects on maternal behavior and function after delivery Dapsone was evaluated. Maternal toxicity (decreased body weight and feeding) and developmental effects (deadborns) at a dapsone dose of 30 mg / kg / day (approximately 560 times the systemic exposure associated with MRHD of Axon gel 7.5% based on AUC comparison) Increased and decreased pup weight). There were no effects on survival, physical development, behavior, learning ability or reproductive function of surviving pups.
14 Clinical Study In a 12-week, multicenter, randomized, double-blind vehicle control study, the safety and efficacy of once-daily use of Axon Gel 7.5% was evaluated. Efficacy was evaluated in a total of 4340 subjects over 12 years of age. The majority of subjects have moderate acne vulgaris at baseline, 20-50 inflammatory lesions and 30-100 non-inflammatory lesions, randomized to Akson Gel 7.5 % Or vehicle received.
The treatment response was determined at week 12 by the percentage of subjects rated “none” or “minimum” with a grade improvement of at least two from baseline in the general acne score (GAAS), as well as inflammation. Defined as mean absolute change from baseline in both sex and non-inflammatory lesion counts. A GAAS score of “none” corresponded to the absence of evidence of acne vulgaris on the face. A “minimal” GAAS score corresponded to the presence of a few non-inflammatory lesions (comedones) and the presence of a few inflammatory lesions (papules / pustules).
The following table shows the GAAS success rate, average reduction, and reduction rate from baseline for the number of acne lesions after 12 weeks of treatment.
16 Supply / Storage and Handling Azone gel is a grayish white to yellow gel containing suspended particles. It is supplied with an airless pump equipped with a high density polyethylene piston and containing a polypropylene bottle.
Axon (Dapson) gel 7.5% is supplied in the following sizes.
NDC0023-5206-30 30 gram pump NDC0023-5206-60 60 gram pump NDC0023-5206-90 90 gram pump Storage: Store at 20-25 ° C (68-77 ° F) and 15-30 ° C (59-86 °) Variations in F) are allowed [see USP regulatory room temperature]. Protect from freezing.
17 Patient counseling information Advise patients to read FDA approved patient displays (patient information).
Hematological effects • Inform the patient that methemoglobinemia may occur with treatment with topical dapsone. Advise patients to get a diagnosis at the hospital immediately if they develop cyanosis [see Warnings and Precautions (5.1)].
Inform patients with G6PD deficiency that hemolytic anemia may occur with treatment with topical dapsone. Advise the patient to get a diagnosis in the hospital if signs and symptoms suggest hemolytic anemia occur [see Warnings and Precautions (5.1)].
IMPORTANT ADMINISTRATION INSTRUCTIONS • Advise the patient to apply Axon Gel 7.5% once a day to the entire face [see Dose and Administration (2)].
・ Axon gel 7.5% is limited to topical use.
・ Do not apply Akzon Gel 7.5% to the eyes, mouth or mucous membranes.

Claims (20)

A method of treating said acne vulgaris in a subject in need of treatment for acne vulgaris, comprising:
Administering a topical pharmaceutical composition comprising about 7.5% by weight dapsone to the entire face of the subject once a day for the duration of treatment effective to improve acne vulgaris;
The duration of the treatment ranges from about 4 weeks to about 12 weeks;
The method is therapeutically effective to reduce the number of facial lesions in the subject;
Said method.   2. The method of claim 1, wherein the topical pharmaceutical composition is free of adapalene.   3. A method according to claim 1 or claim 2, wherein the treatment duration is 12 weeks.   The method of any one of claims 1 to 3, wherein the lesion comprises an inflammatory lesion.   The method of any one of claims 1 to 3, wherein the lesion comprises a non-inflammatory lesion.   6. The method of any one of claims 1-5, wherein the method is effective in reducing the amount of local skin irritation in the subject over the treatment duration.   The method of claim 6, wherein the local skin irritation comprises erythema.   The method of claim 6, wherein the local skin irritation comprises scaling.   The method of claim 6, wherein the local skin irritation comprises dryness.   The method of claim 6, wherein the local skin irritation comprises tingling / burning.   11. The method of any one of claims 1-10, wherein the topical pharmaceutical composition further comprises about 30% by weight diethylene glycol monoethyl ether.   The method according to any one of claims 1 to 11, wherein the topical pharmaceutical composition further comprises 4% by weight of a polymer viscosity improver comprising an acrylamide / acryloyldimethyltaurine sodium copolymer.   The method according to any one of claims 1 to 12, wherein the topical pharmaceutical composition further comprises methylparaben. A method of treating said post-inflammatory pigmentation in a subject in need of treatment of post-inflammatory pigmentation comprising:
A topical pharmaceutical composition comprising about 7.5% by weight dapsone is said face of said subject at a frequency of once a day for a treatment duration effective to reduce the number of dark spots on said subject's face. Including administration to the whole;
The duration of the treatment ranges from about 4 weeks to about 12 weeks;
The method is therapeutically effective in improving the post-inflammatory pigmentation;
Said method.   15. The method of claim 14, wherein the topical pharmaceutical composition is free of adapalene.   16. A method according to claim 14 or claim 15, wherein the treatment duration is 12 weeks.   The method according to any one of claims 14 to 16, wherein the dark spots are completely removed.   18. A method according to any one of claims 14 to 17, wherein the topical pharmaceutical composition further comprises about 30% by weight diethylene glycol monoethyl ether.   The method according to any one of claims 14 to 18, wherein the topical pharmaceutical composition further comprises 4% by weight of a polymer viscosity improver comprising an acrylamide / acryloyldimethyltaurine sodium copolymer.   20. A method according to any one of claims 14 to 19, wherein the topical pharmaceutical composition further comprises methylparaben.